Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
16.59 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
42.5
Modified dose descriptor starting point:
NOAEC
DNEL value:
705.26 mg/m³
Explanation for the modification of the dose descriptor starting point:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.35 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
170
Modified dose descriptor starting point:
NOAEL
DNEL value:
400 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Worker:

Based on the available data “(Z)-4-[C11-13 (branched) alkylamino]-4-oxo-2-butenoic acid”, has to be considered as irritating to the skin (R38 according to Directive 67/548/EEC annex VI; Cat. 2 according to EC/1271/2008), as irritating to the eye (R36/Cat. 2) and potentially skin sensitizing (R43; Cat. 1), respectively.As no dose response information for these local effects exists, the use of protective gloves and appropriate eye protection is mandatory whenever a potential for relevant ocular or dermal exposure exists.

The primary routes of anticipated industrial and professional exposure are via inhalation and skin contact. In industrial settings, ingestion is not an anticipated route of exposure, but has to be considered for the general population (see below).

Dermal short-term and long-term exposure – local effects:

For the sensitization potential, a qualitative assessment was conducted:

Though sensitization reactions of the skin are generally regarded as threshold effect, deriving a threshold and setting a DNEL is very difficult in practice. No dose-response data of the tested substance are on-hand, which would support a quantitative determination of a DNEL as the available LLNA did not allow the calculation of an EC3 value and thus the derivation of a DNEL.

Based on the available LLNA, the test substance is a moderate to strong skin sensitizer.

Therefore the use of gloves is required in order to prevent any skin contact with the test substance and thus the occurrence of skin sensitization.

 

Inhalation long-term exposure – systemic effects:

The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (RTC, 2013) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for general, systemic toxicity of the test substance was 400 mg/kg bw/d for rats.

This point of departure was modified to get the corrected starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, p. 26 f.:

The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 8-hour standard inhalation volume of rats versus humans, and for differences between the 8-hour inhalation volume of workers in rest versus workers in light activity, by multiplying with the corresponding factors (x 1/0.38 m³/kg/d x 6.7 m³/10 m³). The resulting corrected starting point for inhalation DNEL derivation for workers is equal to 705.26 mg/m³.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

-         Remaining differences: 2.5

Recommended in REACh Guidance document R.8 

-         Intraspecies factor: 5

Recommended in REACh Guidance document R.8 

- Exposure duration: 3.4 (Batke et.al., 2011)

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011). In addition females in which the observed effects on reproduction and development occurred were exposed for a longer period of time (at least 42 days instead of 28 days), a factor of 3.4 therefore is sufficient.

- Dose-response: 1

Total AF = 2.5 x 5 x 3.4 x 1 = 42.5

Based on this calculation the resulting DNEL is 16.59 mg/m³.

Dermal long-term exposure – systemic effects:

The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (RTC, 2013) was identified as the appropriate starting point for DNEL derivation for long-term dermal exposure. The NOAEL for general, systemic toxicity of the test substance was 400 mg/kg bw/d for rats.

There is no data available indicating that dermal uptake is considerably lower than oral uptake. The oral systemic long-term NOAEL was therefore considered appropriate for derivation of a dermal systemic long-term DNEL without further correction.

- Interspecies factor: 4

Recommended for the rat in REACh Guidance document R.8 for allometric scaling

-         Remaining differences: 2.5

Recommended in REACh Guidance document R.8 

-         Intraspecies factor: 5

Recommended in REACh Guidance document R.8 

- Exposure duration: 3.4 (Batke et.al., 2011)

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011). In addition females in which the observed effects on reproduction and development occurred were exposed for a longer period of time (at least 42 days instead of 28 days), a factor of 3.4 therefore is sufficient.

- Dose-response: 1

Total AF = 4 x 2.5 x 5 x 3.4 x 1 = 170

Based on this calculation the resulting DNEL is 2.35 mg/kg bw/day.

 

- Batke M, Escher S, Hoffmann-Doerr S, Melber C, Messinger H, Mangelsdorf I.(2011).Evaluation of time extrapolation factors based on the database RepDose. Toxicology Letters 205 (2011) 122– 129.

 

- Escher S and Mangelsdorf I. (2009). Evaluation of risk assessment factors for inter-species and time-extrapolation. Toxicol Lett 189:S247-S248. 46th Congress of the European Societies of Toxicology, 13-16 September 2009, Dresden.

 

 - Bitsch A, Jacobi S, Melber C, Wahnschaffe U, Simetska N, Mangelsdorf I. (2006).REPDOSE: A database on repeated dose toxicity studies of commercial chemicals – a multifunctional tool. Regul Toxicol Pharmacol 46:202-210.

-ECHA (2008). REACh Guidance document R.8

-ECETOC (2003). Derivation of Assessment factors for Human Health Risk Assessment. Technical Report No. 86, February 2003.

-ECETOC (2010). Guidance on Assessment Factors to Derive DNELs.Technical Report No. 110, October 2010.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.09 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
85
Modified dose descriptor starting point:
NOAEC
DNEL value:
347.82 mg/m³
Explanation for the modification of the dose descriptor starting point:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.17 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
340
Modified dose descriptor starting point:
NOAEL
DNEL value:
400 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.17 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
340
Modified dose descriptor starting point:
NOAEL
DNEL value:
400 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

Consumer

Based on the available data “ (Z)-4-[C11-13 (branched) alkylamino]-4-oxo-2-butenoic acid”, has to be considered as irritating to the skin (R38 according to Directive 67/548/EEC annex VI; Cat. 2 according to EC/1271/2008), as irritating to the eye (R36/Cat. 2) and potentially skin sensitizing (R43; Cat. 1), respectively.As no dose response information for these local effects exists, the use of protective gloves and appropriate eye protection is mandatory whenever a potential for relevant ocular or dermal exposure exists.

For the general population, all three possible routes of exposure (oral, dermal, inhalation) have to be taken into account.

Dermal short-term and long-term exposure – local effects:

For the sensitization potential, a qualitative assessment was conducted:

Though sensitization reactions of the skin are generally regarded as threshold effect, deriving a threshold and setting a DNEL is very difficult in practice. No dose-response data of the tested substance are on-hand, which would support a quantitative determination of a DNEL as the available LLNA did not allow the calculation of an EC3 value and thus the derivation of a DNEL.

Based on the available LLNA, the test substance is a moderate to strong skin sensitizer.

Therefore the use of gloves is required in order to prevent any skin contact with the test substance and thus the occurrence of skin sensitization.

Inhalation long-term exposure – systemic effects:

The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (RTC, 2013) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for general, systemic toxicity of the test substance was 400 mg/kg bw/d for rats.

This point of departure was modified to get the correct starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, p. 26 f.:

The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 24-hour standard inhalation volume of rats versus humans by multiplying with the corresponding factor (x 1/1.15 m³/kg/d). The resulting corrected starting point for inhalation DNEL derivation for the general population is equal to 347.82 mg/m³.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

-         Remaining differences: 2.5

Recommended in REACh Guidance document R.8 

-         Intraspecies factor: 10

Recommended in REACh Guidance document R.8 

- Exposure duration: 3.4 (Batke et.al., 2011)

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011). In addition females in which the observed effects on reproduction and development occurred were exposed for a longer period of time (at least 42 days instead of 28 days), a factor of 3.4 therefore is sufficient.

- Dose-response: 1

Total AF = 2.5 x 10 x 3.4 x 1 = 85

Based on this calculation the resulting DNEL is 4.09 mg/m³.

Dermal long-term exposure – systemic effects:

The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (RTC, 2013) was identified as the appropriate starting point for DNEL derivation for long-term dermal exposure. The NOAEL for general, systemic toxicity of the test substance was 400 mg/kg bw/d for rats.

There is no data available indicating that dermal uptake is considerably lower than oral uptake. The oral systemic long-term NOAEL was therefore considered appropriate for derivation of a dermal systemic long-term DNEL without further correction.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

- Interspecies factor: 4

Recommended for the rat in REACh Guidance document R.8 for allometric scaling

-         Remaining differences: 2.5

Recommended in REACh Guidance document R.8 

-         Intraspecies factor: 10

Recommended in REACh Guidance document R.8 

- Exposure duration: 3.4 (Batke et.al., 2011)

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011).

- Dose-response: 1

Total AF = 4 x 2.5 x 10 x 3.4 x 1 x 1 = 340

Based on this calculation the resulting DNEL is 1.17 mg/kg bw/day.

Oral long-term exposure – systemic effects:

The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (RTC, 2013) was identified as the appropriate starting point for DNEL derivation for long-term oral exposure. The NOAEL for general, systemic toxicity of the test substance was 400 mg/kg bw/d for rats.

The NOAEL of 125 mg/kg bw/day was considered appropriate as point of departure for DNEL derivation.

Subsequently, the following assessment factors are taken into account for the final DNEL calculation for the oral route: interspecies differences (4), remaining differences (2.5), intraspecies differences (10), exposure duration (3.4) (AF = 4 x 2.5 x 10 x 3.4 x 1 = 340).

As a consequence, the resulting DNEL for long-term oral local and systemic effects is 1.17 mg/kg bw/d for the general population.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

- Interspecies factor: 4

Recommended for the rat in REACh Guidance document R.8 for allometric scaling

-         Remaining differences: 2.5

Recommended in REACh Guidance document R.8 

-         Intraspecies factor: 10

Recommended in REACh Guidance document R.8 

- Exposure duration: 3.4 (Batke et.al., 2011)

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011).

- Dose-response: 1

 

- Batke M, Escher S, Hoffmann-Doerr S, Melber C, Messinger H, Mangelsdorf I.(2011).Evaluation of time extrapolation factors based on the database RepDose. Toxicology Letters 205 (2011) 122– 129.

 

- Escher S and Mangelsdorf I. (2009). Evaluation of risk assessment factors for inter-species and time-extrapolation. Toxicol Lett 189:S247-S248. 46th Congress of the European Societies of Toxicology, 13-16 September 2009, Dresden.

 

- Bitsch A, Jacobi S, Melber C, Wahnschaffe U, Simetska N, Mangelsdorf I. (2006).REPDOSE: A database on repeated dose toxicity studies of commercial chemicals – a multifunctional tool. Regul Toxicol Pharmacol 46:202-210.

-ECHA (2008). REACh Guidance document R.8

-ECETOC (2003). Derivation of Assessment factors for Human Health Risk Assessment. Technical Report No. 86, February 2003.

-ECETOC (2010). Guidance on Assessment Factors to Derive DNELs.Technical Report No. 110, October 2010.